Other Conditions of Brain
Conditions
Brief summary
Repetitive transcranial magnetic stimulation (rTMS) uses a magnetic field to non-invasively induce electrical function within the brain. Stimulation allows brain cells to change the way that they adapt and communicate with each other, known as 'synaptic plasticity'. It is thought that alterations in these adaptive brain changes underlie the ability of rTMS to treat mental illnesses like depression. The regulation of synaptic plasticity is complex, and involves multiple interacting factors and redundant systems to ensure that plasticity is carefully regulated. To date, studies attempting to alter impact synaptic plasticity have done so using pharmacological adjuncts that target extracellular contributions to plasticity. Here, we propose the first proof of principle study targeting intracellular regulation of plasticity by using a pharmacological adjunct targeting Phosphodiesterase 4 (PDE4), a key regulator a cyclic AMP gradients in brain cells. We will pair TMS with electromyography (EMG) to measure activity dependent changes in the motor cortex following rTMS to test the ability of a PDE4 inhibition to enhance synaptic plasticity after rTMS.
Detailed description
This study will employ a randomized, placebo-controlled single-blind crossover trial of adjunctive roflumilast with intermittent or continuous theta burst (iTBS/cTBS) TMS to the primary motor cortex. Participants will complete a screen visit to determine eligibility based on the inclusion/exclusion criteria. If the participants are not eligible, no further study procedures will be conducted. Randomization with allocation concealment of eligible patients to begin with either the study medication or placebo arm of the study will involve a random number sequence generated a priori with atmospheric noise, with single-blind random condition assignment and allocation concealment. Baseline corticospinal excitability will be quantified. One hour following ingestion of the blinded capsule iTBS/cTBS will be applied to the primary motor cortex, and the response will be quantified through a combination of motor evoked potentials (MEPs) at a fixed stimulus intensity, cortical silent period, and a range of stimuli to generate stimulus response curves (SRCs). The duration of each arm is up to 2.5 hours, and they will be separated by at least 1 week. All participants will complete a questionnaire to assess any side effects (emotional and physical) following each rTMS session.
Interventions
DRUGRoflumilast
Participants will ingest either a placebo or roflumilast 500mg in a single blind crossover study and receive transcranial magnetic stimulation to the primary motor cortex.
DRUGPlacebo
Participants will ingest either a placebo or roflumilast 500mg in a single blind crossover study and receive transcranial magnetic stimulation to the primary motor cortex.
DEVICEIntermittent theta-burst stimulation transcranial magnetic stimulation
Intermittent theta-burst stimulation consists of 2 second trains every 10 seconds. Each train is composed of 3 pulses at 50Hz, 200 milliseconds intervals given at 80% resting motor threshold. The total time for this treatment stimulus is 600 pulses over 190 seconds.
DEVICEContinuous theta-burst stimulation transcranial magnetic stimulation
Continuous theta-burst stimulation consists of 2 second trains every 10 seconds. Each train is composed of 3 pulses at 50Hz, 200 milliseconds intervals given at 80% resting motor threshold. The total time for this treatment stimulus is 600 pulses over 40 seconds.
Sponsors
University of Calgary
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
DOUBLE (Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 60 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy individuals (no chronic medical conditions). 2. Aged 18-60 years.
Exclusion criteria
1. Pregnancy 2. Lactation 3. Epilepsy 4. Previous stroke 5. Current Renal Disease 6. Current Liver Disease 7. Allergy to roflumilast or any of its non-medicinal ingredients 8. Current psychiatric concerns 9. Currently taking any medications with known serious interactions with roflumilast (abametapir, apalutamide, dabrafenifb, enzalutamide, fexinidazole, idelalisib, ivosidenib, lonadarnib, ritonavir, secobarbital, tucatinib, and voxelotor).Intracranial metallic objects (dental hardware is not an exclusionary criterion) 10. Substance use disorder 11. The inability to refrain from alcohol use for 24 hours prior to stimulation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Motor evoked potential amplitude | -5 minutes, -10minutes, -5 minutes, and immediately prior to theta-burst stimulation, then +5 minutes, +10 minutes, +15 minutes, +20 minutes, +25 minutes, +30 minutes, +45 minutes and +60 minutes after theta-burst stimulation. | Motor evoked potentials will be measured using surface electrodes placed over the first dorsal interosseous muscle of the hand to a single stimulus intensity of 120% of resting motor threshold. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Cortical silent period | Baseline, 30 minutes following theta-burst stimulation, 60 minutes following theta-burst stimulation. | Motor evoked potentials will be measured using surface electrodes placed over the first dorsal interosseous muscle while participants maintain a light contracture of the muscle. |
| Motor evoked potential stimulus response curve | Baseline, 30 minutes following theta-burst stimulation, 60 minutes following theta-burst stimulation. | Motor evoked potentials will be measured using surface electrodes placed over the first dorsal interosseous muscle to varying stimulus intensities. |
Countries
Canada
Outcome results
None listed